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Life-threatening COVID-19–Related Disease of Children Driven by Loss of Gut Barrier

Key findings

  • This study was the first to investigate the role of the gastrointestinal tract in the pathogenesis of multisystem inflammatory syndrome in children (MIS-C)
  • SARS-CoV-2 RNA was detected in stool samples of the majority of patients with MIS-C at 13–62 days after exposure or infection
  • Loss of gut mucosal barrier integrity, indicated by increased levels of zonulin (a family of proteins that regulate intestinal permeability) and two markers of microbial translocation, coincided with the presence of SARS-CoV-2 antigens in the bloodstream
  • A 17-month-old child critically ill with MIS-C improved when treated with larazotide, an investigational zonulin antagonist, providing proof of concept that zonulin antagonism may directly reduce SARS-CoV-2 antigenemia

The prevalence of infection with the SARS-CoV-2 coronavirus is increasing among children and adolescents. Accordingly, multisystem inflammatory syndrome in children (MIS-C), the life-threatening immune activation syndrome associated with prior SARS-CoV-2 infection or exposure, is also increasingly common.

In adults, it's becoming clear that the gut is a central point for SARS-CoV-2 infection and dysbiosis, and that disruption of the gastrointestinal (GI) barrier drives inflammatory activation in severe COVID-19. Now, Lael M. Yonker, MD, director of the Cystic Fibrosis Center in the Department of Pediatrics and investigator in the Mucosal Immunology and Biology Research Center at MassGeneral Hospital for Children, Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center, David R. Walt, PhD, of the Department of Pathology at Brigham and Women's Hospital, and colleagues have become the first to evaluate the role of the gastrointestinal tract in the pathogenesis of MIS-C.

In the Journal of Clinical Investigation, the team reports the first evidence of prolonged exposure to SARS-CoV-2 in the GI tract of children with MIS-C, which coincides with loss of gut mucosal barrier integrity.

Study Cohorts

The researchers analyzed blood and stool specimens from:

  • 19 children diagnosed with MIS-C (13–62 days from SARS-CoV-2 exposure/infection; 89% with GI symptoms, most unusually severe)
  • 26 children with PCR-confirmed COVID-19 (0–10 days from exposure/infection; 27% with GI symptoms)
  • 55 controls without COVID-19 (32 hospitalized prior to the pandemic)

SARS-CoV-2 in the GI Tract

The researchers detected measurable loads of SARS-CoV-2 RNA in stool from MIS-C patients, even weeks after initial infection/exposure. The gut appears to be an ongoing locus of an infection in MIS-C.

Loss of Intestinal Mucosal Barrier Function

Children with MIS-C, but not those with acute COVID-19, had significantly increased blood levels of markers of gastrointestinal barrier integrity, including:

  • Zonulin, a family of proteins that regulate intestinal permeability
  • Lipopolysaccharide binding protein and soluble CD14, which are markers of microbial translocation

These findings suggest that in children with MIS-C, the intestinal mucosal barrier does not prevent the passage of large antigens from the gut lumen into the bloodstream, including antigens derived from SARS-CoV-2.

Bloodborne Antigens

Plasma levels of the SARS-CoV-2 spike protein and the S1 subunit of the spike protein were significantly higher in patients with MIS-C than in healthy controls or children with acute COVID-19. This can be attributed to leakage from the GI system.

The spike antigen rose during the first few days of MIS-C symptoms and persisted for more than 10 days—occasionally through six months—despite the presence of antibodies. Furthermore, antigen levels did not significantly decrease after initiation of steroid and/or immunoglobulin replacement therapy, the only currently recommended treatments for MIS-C.

In children with MIS-C, antibodies continued to rise in response to antigen. In fact, plasma values of anti–spike-IgA remained elevated for months after the initial SARS-CoV-2 infection. This suggests ineffective adaptive immunity plus ongoing antigen release from increased intestinal permeability.

Zonulin Antagonist Therapy for a Toddler

Larazotide, an investigational zonulin antagonist, is in phase 3 trials for the treatment of refractory celiac disease. Mass General obtained FDA approval for compassionate use of larazotide to treat a critically ill, medically complex 17-month-old boy with MIS-C after he failed to improve with anti-inflammatory therapies.

After initiation of larazotide, the child's SARS-CoV-2 antigen levels dropped precipitously (by 90% for spike protein and 98% for the nucleocapsid protein) along with improvement in inflammatory mediators. He achieved his longest stretches without fever since admission, he was able to resume full feeds and his ventilatory status improved.

Toward the Future

Current treatments for MIS-C aim to dampen the inflammatory response but do not address mucosal permeability or antigenemia. The results of this study suggest several other strategies:

  • Preventing mucosal damage early in the course of SARS-CoV-2 infection may prevent the development of MIS-C
  • Increased levels of zonulin in children recently infected with SARS-CoV-2 may identify those at increased risk of developing MIS-C
  • Detection of bloodborne antigen and zonulin within the first few days after MIS-C symptom onset might confirm that a patient has MIS-C

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